The present invention relates to a sequence for the preparation of amino acids, for example alpha-amino acids, in particular methionine, by making use of an amidocarbonylation reaction. During the process, an N-acyl amino acid is synthesised in an amidocarbonylation reaction by making use of a catalyst, and this N-acyl amino acid is then subsequently hydrolysed to the desired amino acid while the carboxylic acid thereby formed is reconverted to the corresponding carboxylic acid amide by reaction with ammonia, followed by dehydration. This carboxylic acid amide can then be re-introduced as a starting material in the initial amidocarbonylation reaction step. According to the invention, the catalyst used during the first reaction step can be recovered and recycled into the first reactor vessel. The synthesis can be conducted in a batch, semi-batch or preferably in a continuous manner.
Amino acids are important products and are correspondingly used in a variety of applications, such as human medicine, the pharmaceuticals industry as well as in the synthesis of a plurality of fine chemicals and active ingredients. In particular they are used as additives in the fodder of many livestock in enantiomerically pure form, but also in the racemic form.
Several methods are employed on an industrial scale to prepare amino acids, such as biotechnological processes, as for example fermentation processes, and hydrolysis of proteins. Chemical syntheses are also used for producing amino acids. One possibility is the Strecker reaction or its variants, such as the Bucherer-Bergs reaction. Still further, the amidocarbonylation reaction is also known to be used for preparing amino acids.
The amidocarbonylation reaction was discovered by Wakamatsu, et al. in 1971 and is disclosed in the German patent application DE-A-2115985. The reaction is catalysed by various transition metal compounds and is a three component reaction between a carboxylic acid amide, an aldehyde and carbon monoxide, either in a pure form or as a mixture with hydrogen (synthesis gas) (see Scheme 1).

One should bear in mind that the utilisation of the amidocarbonylation reaction is to be regarded as advantageous in comparison to the conventional Strecker synthesis of amino acids or its variants since the amidocarbonylation requires carbon monoxide instead of hydrogen cyanide as one of its integral raw materials. This is of considerable advantage due to the higher price and in particular due to the high toxicity of hydrogen cyanide.
The products of the amidocarbonylation reaction are N-acyl amino acids, having the general formula:R1—CH(NH—CO—R2)COOH
R1 is: hydrogen, a linear, branched or cyclic alkyl group that has from 1 to 10 carbon atoms, especially 1 to 7, or                a linear or branched alkyl group that has from 1 to 10, especially 1 to 6 carbon atoms containing a substituent(s) amido, amino, monoalkylamino, dialkylamino, monoalkylamido, dialkylamido alkoxy, alkylthio, hydroxy, thiol, carboxylic acid or carboxylic acid alkyl ester group(s), or a 1H-imidazole-, phenyl- or 3′-indolyl-, p-hydroxyphenyl or p-alkoxyphenyl residue, whereby the said alkyl or alkoxy group has 1 to 3 carbon atoms,        most preferred for R1 is a linear or branched alkyl group that has from 1 to 10, especially 1 to 6 carbon atoms containing a substituent(s) amido, alkoxy, alkylthio or a phenyl or p-alkoxyphenyl residue, whereby the said alkyl group(s) has 1 to 3 carbon atoms.        
R2 is: hydrogen or a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, or                a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, containing a substituent(s) amido, monoalkylamido, dialkylamido hydroxy, alkyoxy, thioalkoxy group(s) or        a substituted or non-substituted aryl or benzyl group, where the substituent(s) may be a hydroxy, alkoxy, fluoro, chloro, bromo or a trialkylamino group, whereby the said alkyl group has 1 to 3 carbon atoms.        
The said N-acyl amino acids are starting materials especially for the α-amino acids:
asparagine, aspartic acid, cystein, glutamine, glutamic acid, histidine, serine, threonine, tryptophan, tyrosine, most especially for alanine, glycine isoleucine, leucine, methionine, phenylalanine, valine.
Substituted hydantoins can also be prepared instead of N-acyl amino acids. In such a case, ureas are used as starting materials, as for example disclosed in the European patent application EP 1 048 656 A2.
The European patent application EP 338 330 A1 and the German patent application DE 19629717 also disclose the synthesis of various N-acyl amino acids via the amidocarbonylation reaction. DE 4415312 and DE 19545641 deal with that reaction as well, for example in the case of the industrial preparation of sarcosinates.
However, no prior art suggests a process to prepare amino acids, in particular methionine, comprising of the amidocarbonylation reaction with convenient withdrawal of the used catalyst, hydrolysis of the N-acyl amino acid formed, and conversion of the by-product carboxylic acid formed during the hydrolysis into a carboxylic acid amide.
With regard to this, one should note that the aspect of catalyst recycling of the expensive transition metal catalyst used in the amidocarbonylation is also an important target from an economic point of view, that is avoiding the high costs involved in the acquisition of new catalyst and the disposal of spent catalyst. Recycling of the catalyst is furthermore advantageous with respect to environmental reasons due to the often high toxicity of transition metals and compounds related thereto.
A process for the recovery of cobalt carbonyl catalysts is, for example, described in the European patent EP 779 102 B1. According to that prior art, the active catalyst was initially oxidised after the reaction to the more stable cobalt (II) form, which was then extracted into aqueous solution, precipitated as the hydroxide and subsequently converted into a melt consisting of the hydroxide and N-acyl amino derivative which can be used for regeneration of the active catalyst under a synthesis gas atmosphere.
However, the same disadvantage as mentioned above occurs according to that prior art. For example, handling problems occur during the precipitation and drying of cobalt hydroxide. Still further, if the process were to be run in a continuous way, higher expenses would be incurred. Summing up, the processes suggested in the prior art for catalyst recovery during an amidocarbonylation reaction are not suitable for the large scale industrial synthesis of amino acids, especially methionine, due to the variety of handling problems, occurring in particular for such amino acids containing sulphur, as methionine.
There is, however, a strong need to find a way to recycle the catalyst used during the synthesis of amino acids via the amidocarbonylation. The carbonyl catalyst makes it possible to make use of carbon monoxide as a starting material, which is easier to handle and more widely available than hydrogen cyanide.